β-Lactam antibiotics have been widely used for the treatment of bacterial infections both in hospitals and in the general public. There are several classes of β-lactam antibiotics that have found clinical application, these include the penicillins, cephalosporins, cephamycins, carbacephems, oxacephems, carbapenems and monobactams.
The efficiency of all of these classes to cure bacterial infections has been impaired by the appearance of bacteria that are resistant towards the antibiotics. The prevalent cause of this resistance in Gram-negative bacteria is the expression by the bacteria of enzymes known as β-lactamases that are able to hydrolyse the β-lactam antibiotics rendering them inactive. Bacteria are able to produce a variety of β-lactamases, including penicillinases, cephalosporinases, cephamycinases, carbapenemases, monobactamases, broad-spectrum β-lactamases and extended-spectrum β-lactamases.
The possibility of rescuing individual β-lactam antibiotics by combination with a β-lactamase inhibitor that inactivates the β-lactamase before it can hydrolyse the β-lactam antibiotic has been demonstrated with clinically useful combinations between penicillins such as amoxicillin, ampicillin and ticarcillin and β-lactamase inhibitors such as clavulanic acid, sulbactam and tazobactam. Further, potential combinations have been described involving cephalosporins and newly developed β-lactamase inhibitors including bridged monobactams, penam sulfones, phosphonate esters, exomethylene penams and diazabicyclooctane derivatives.
Monobactams have been regarded as stable towards many β-lactamases. However, there are now many strains of Gram-negative bacteria that exhibit β-lactamase-mediated resistance towards the monobactam antibiotics (aztreonam, carumonam and tigemonam).
The present invention aims to provide improved medicaments with novel monobactam antibiotics and combinations of monobactam antibiotics with β-lactamase inhibitors that are active against aerobic Gram-negative bacteria that are resistant against treatments with monobactam antibiotics.